Dialysis patients have severe exercise limitations related to metabolic disturbances, but muscle fatigue has not been well studied in this population. The purpose of this study was to investigate the magnitude and mechanisms of fatigue of the ankle dorsiflexor muscles in patients on maintenance hemodialysis. Thirty-three dialysis patients and 12 healthy control subjects performed incremental isometric dorsiflexion exercise (4 s contract, 6 s relax), beginning at 10% of their maximal voluntary contraction (MVC) and increasing by 10% every 2 minutes. Muscle fatigue (fall of MVC), the completeness of voluntary activation, and the metabolic responses to exercise were measured. Before exercise, dialysis subjects exhibited reduced strength and evidence of impaired peripheral activation (lower compound muscle activation potential [CMAP] amplitude) but no evidence of metabolic perturbation. During exercise, dialysis subjects demonstrated 3-fold greater fatigue than controls with evidence of central activation failure but no change in peripheral activation. All metabolic parameters were significantly more perturbed at end-exercise in dialysis subjects than controls, including lower PCr and pH, and higher Pi, Pi/PCr, and H₂PO₄^-. Oxidative potential was markedly lower in patients than controls (62.5 ± 27.2 vs. 134.6 ± 31.7, p<0.0001). Muscle fatigue was negatively correlated with oxidative potential among dialysis subjects (r=-0.52, p=0.04) but not control subjects (r=-0.26, p=0.53). Changes in central activation ratio (CAR) were also correlated with muscle fatigue in the dialysis (r=0.59, p=0.001) but not the control (r=0.23, p=0.50) group. This study provides new information regarding the excessive muscular fatigue of dialysis patients and demonstrates that the mechanisms of this fatigue include both intramuscular energy metabolism and central activation failure.